MX2012013933A

MX2012013933A - Pharmaceutical formulations of statins and omega-3 fatty acids for encapsulation.

Info

Publication number: MX2012013933A
Application number: MX2012013933A
Authority: MX
Inventors: Peter Draper; Beth Okutan; James Draper
Original assignee: Accucaps Ind Ltd
Priority date: 2010-06-03
Filing date: 2011-06-03
Publication date: 2013-02-11
Also published as: PL2575787T3; EP2575787A4; EP3581173A1; EP2575787B1; MX2019013095A; JP5972261B2; CA2706270A1; EP2575787A1; CA2706270C; PT2575787T; JP2016138143A; HUE050830T2; JP2013527205A; AU2011261117A1; US20230233472A1; ES2807498T3; MX369477B; WO2011150505A1; AU2011261117B2; US20130115281A1

Abstract

A multi phase soft gelatin dosage form comprising at least one preformed solid dosage form comprising a statin compound and at least one liquid fill phase comprising Omega-3 fatty acids. The multi phase soft gelatin dosage forms of the present invention are especially useful to combine at least one solid dosage form and at least one liquid phase for single ingestion. The solid phase, liquid phase or coatings may further comprise active pharmaceutical ingredients, nutraceuticals, nutritional supplements, or therapeutic substances, functional excipients or combinations thereof.

Description

PHARMACEUTICAL FORMULATIONS OF STATINES AND OMEGA-3 FATTY ACIDS FOR ENCAPSULATION FIELD OF THE INVENTION The present invention relates generally to soft gelatin dosage forms for oral administration comprising multiple phases. More particularly, the present invention relates to pharmaceutical compositions in unit dosage form comprising soft gelatine capsules containing an oil phase and at least one HMG-CoA reductase inhibitor in solid form within the oil phase.

BACKGROUND OF THE INVENTION Statins are a class of drugs for the treatment of hypercholesterolemia and hyperlipidemia, which are known risk factors for atherosclerosis and coronary heart disease. It is well known that statins inhibit the enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which forms cholesterol in the liver. The administration of statins or HMG-CoA reductase inhibitors has been shown to lower cholesterol levels.

Statins can be found in the form of acid or lactone form. It is generally known that statins become unstable when exposed to heat, humidity, low pH and light. For example, statins are susceptible to interconversion between their forms of hydroxy acid and lactone in an acidic environment. Acid forms can also be converted to lactone forms through hydrolysis.

It is well known that one form can provide better inhibition of cholesterol biosynthesis than the other. Thus, the interconversion of statin compounds between the forms of hydroxy acid and lactone is undesirable. Due to the instability of statins, it is desirable to provide stable formulations of statins to prevent statins. degradation or interconversion. Tablets compositions of statin compounds address stability problems by incorporating anhydrous and alkaline excipients. In addition, statin tablets are typically film coated with a cellulose derivative or similar coating to provide a moisture barrier.

The commercially available statin compounds are in tablet dosage form and include LIPITORMR or TORVASTMR (atorvastatin calcium) sold by Pfizer, LESCOLMR or LESCOL XLR (fluvastatin sodium) sold by Novartis, MEVACORMR, ALTOCORMR or ALTOPREVMR (lovastatin) sold by Merck, LIVALOMR or PITAVAMR (pitavastatin) sold by Kowa, PRAVACHOLMR, SELEKTINEMR or LIPOSTATMR (pravastatin sodium) sold by Bristol Myers Squibb, CREST0RMR (rosuvastatin calcium) sold by AstraZeneca and ZOCORMR or LIPEXMR (simvastatin) sold by Merck. Examples of established tablet dosage forms containing statin compounds with an additional active ingredient include VYORTIN ™ (simvastatin and exetimibe) sold by Merck, ADVICORM ™ (lovastatin and niacin) sold by Merck, CADUET ™ (atorvastatin calcium and amlodipine besylate) sold by Pfizer, and SIMCORMR (simvastatin and niacin) sold by Merck.

The incorporation of statin compounds in soft gelatin filling formulations has additional challenges. Statin compounds formulated in a liquid fill formulation are highly susceptible to interconversion due to moisture and pH. Statin compounds are also incompatible with most of the common ingredients of soft gelatin stuffing and cover ingredients. Thus, due to problems of stability and incompatibility, statin compounds are not suitable for formulation in soft gelatin dosage forms.

Omega-3 fatty acids are well known to help reduce the risk factors for heart disease, including high cholesterol and high blood pressure. Omega-3 fatty acids are often administered as part of a standard treatment for patients with high cholesterol. Omega-3 fatty acids are typically formulated in dosage forms of soft gelatin capsules.

A common drug regimen for high cholesterol includes the combined administration of statins and a high potency omega-3 oil, such as Lovaza ™ by GlaxoSmithKline. Statins and omega-3 oils are administered as separate individual dosage forms.

The ability to incorporate a statin and omega-3 oil in a stable dosage form offers several advantages. The advantages include the convenient supply of multiple medications, the avoidance of potential errors by the user if many medications are to be taken in a single day, increased user compliance, possible synergistic effect and possible controlled delivery.

Attempts have been made to combine a statin and omega-3 oil in a single dosage form. In United States Patent Application Publication No. 2007/0212411 to Fawzy, soft coated gelatin capsules are disclosed. In particular, omega-3 oils are contained within the soft gelatin capsules. The capsules can be coated with a coating comprising a statin mixed with a coating material. Since the statins should be mixed with a coating material and then sprayed onto the capsule to form a coating, the established pharmaceutical characteristics, the active ingredient release profile, bioavailability and performance. of statins are not retained. In addition, in Fawzy, complicated processing steps are required to obtain the statin and omega-3 oil in a single dosage form.

There is still a need for soft gelatine dosage forms containing a statin compound in solid dosage form and the omega-3 oil filling phase which maintains the chemical stability of each phase and prevents any chemical reaction between the multiple phases. It is desirable to incorporate preformed solid dosage forms to retain the established pharmaceutical characteristics of the preformed solid dosage form in combination with a liquid phase, such as physical and chemical stability, release profile of the active ingredient from the solid dosage form, bioavailability. and clinical performance.

BRIEF DESCRIPTION OF THE INVENTION In accordance with one aspect of the present invention, soft phase multi-phase gelatin dosage forms containing at least one liquid phase comprising an Omega-3 oil and at least one solid phase comprising a statin compound are provided.

It is a further aspect of the present invention to produce soft gelatine dosage forms which provide a single ingestion of the multiple dosage forms, each having different phases.

The invention further provides soft gelatine dosage forms containing a solid dosage form and the liquid filling phase which maintains the chemical stability of each phase and prevents any chemical reaction between the multiple phases.

It is a further aspect of the present invention to incorporate preformed solid dosage forms into soft gelatin dosage forms. This capability retains the established pharmaceutical characteristics of the preformed solid dosage form in combination with a liquid phase, such as physical and chemical stability, release profile of the active ingredient from the solid dosage form, bioavailability and clinical performance.

In accordance with one aspect of the present invention, there is provided a multi-phase soft gelatin capsule for oral administration comprising at least one preformed solid dosage form comprising a statin compound and at least one liquid filling phase which It comprises omega-3 fatty acids. The at least one solid dosage form and the at least one liquid filling phase are introduced independently into the soft gelatin capsule.

In one embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one preformed solid dosage form is a pharmaceutical grade finished dosage form.

In one embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein at least one preformed solid dosage form is selected from the group consisting of a tablet, a tablet, a capsule, a portion of solid material and a granule.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one liquid filling phase further comprises at least one additional active ingredient.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one additional active ingredient in the at least one liquid filling phase is selected from the group consisting of: active pharmaceutical ingredient, nutraceutical, nutritional supplement, therapeutic substance, functional excipients and combinations thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one liquid filler phase further comprises extender oils.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the extender oils comprise vegetable oils, mineral oils, food grade oils, pharmaceutically acceptable oils or mixtures thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is selected from the group consisting of: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and salts pharmaceutically acceptable thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is atorvastatin calcium.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is fluvastatin sodium.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is pravastatin sodium.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is rosuvastatin calcium.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound further comprises at least one additional active ingredient.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one additional active ingredient of the statin compound is an active pharmaceutical ingredient.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is simvastatin, and the at least one additional active ingredient is exoimimibe.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is lovastatin and the at least one additional active ingredient is niacin.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is atorvastatin calcium and the at least one additional active ingredient is amlodipine besylate.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the statin compound is simvastatin, and the at least one additional active ingredient is niacin.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein at least one preformed solid dosage form has at least one coating.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one coating on the at least one preformed solid dosage form is selected from the group consisting of: immediate release, protective coatings, enteric or delayed release coatings, sustained release coating, barrier coating, moisture protection coatings and combinations thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one coating on the at least one preformed solid dosage form is selected from the group consisting of: film coating , gelatin coating and combinations thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein at least one coating on the at least one preformed solid dosage form further comprises at least one active ingredient.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one active ingredient of the at least one coating on the at least one preformed solid dosage form is selected from the group consisting of: an active pharmaceutical ingredient, nutraceutical, nutritional supplement, therapeutic substance, functional excipients and combinations thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the omega-3 fatty acids comprise triglycerides, ethyl esters or an emulsified formulation of the omega-3 fatty acids.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the omega-3 fatty acids comprise eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or a mixture thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the soft gelatin capsule has at least one coating.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one coating on the soft gelatin capsule is selected from the group consisting of: immediate release coatings, protective coatings , enteric or delayed release coatings, sustained release coating, barrier coatings, and combinations thereof.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one coating on the soft gelatin capsule further comprises at least one active ingredient.

In another embodiment of the present invention, there is a soft gelatin capsule as defined above, wherein the at least one active ingredient of the at least one coating on the soft gelatin capsule is selected from the group consisting of: an active pharmaceutical ingredient, nutraceutical, nutritional supplement, therapeutic substance, functional excipients and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of soft gelatin capsules according to the invention.

DETAILED DESCRIPTION The present invention provides a soft gelatin capsule containing a solid phase comprising a statin and at least one oil phase. The solid phase and one or more liquid phases are encapsulated inside a soft gelatin capsule. A soft gelatin dosage form is provided for the combined administration of unit doses of statin compounds or statin compounds in combination with other active ingredients and omega-3 fatty acids. Established unit dosage forms of the statin compounds include tablets or capsules containing single ingredient statins or statins in combination with other active ingredients.

The soft gelatin dosage forms of the present invention are capable of delivering multiple medications or therapeutic substances in a single dose, and provide the capabilities for the design of pharmaceutical delivery systems that provide differential release of medications or therapeutic substances from each phase . The multi-phase soft gelatin dosage forms of the present invention are especially useful for combining two or more phases for a single ingestion, where at least one is a solid phase and at least one is a liquid phase. The incorporation of a solid dosage form preformed into a soft gelatin capsule allows the retention of the established pharmaceutical characteristics of the solid dosage form.

The solid phase may be in the form of preformed tablets, tablets, capsules, solid portions, granules or other solid dosage forms. Preferred, the solid phase is comprised of a preformed solid dosage form. More preferably, the preformed solid dosage form is a finished pharmaceutical dosage form, which is a suitable dosage form for administration to a human or animal subject, the pharmaceutical characteristics of which are acceptable and can be approved by the authorities. regulators previously or subject to estimation through regulatory agencies.

The solid phase may consist of a statin compound of a single active ingredient or a combination of a statin compound and another active pharmaceutical ingredient. Statin compounds include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts thereof.

The commercially available single active ingredient statin compounds include LIPIT0RMR or TORVASTMR (atorvastatin calcium) sold by Pfizer, LESCOLMR or LESC0LMR XL (fluvastatin sodium) sold by Novartis, MEVAC0RMR ALTOCORMR or ALT0PREVMR (lovastatin) sold by Merck, LIVALOMR or PITAVAMR ( pitavastatin) sold by Kowa, PRAVACHOLMR, SELEKTINEMR or LIPOSTATMR (pravastatin sodium) sold by Bristol Myers Squibb, CRESTORMR (rosuvastatin calcium) sold by AstraZeneca, ZOCORMR and LIPEXMR (simvastatin) sold by Merck. These commercially available statin compounds are sold as film-coated tablets.

The solid phase of the present invention may include a solid dosage form comprising a combination of a statin compound and another active pharmaceutical ingredient. For example, commercially available statin combination products include, but are not limited to, VYORTIN ™ (simvastatin and exetimibe) sold by Merck, ADVICORM ™ (lovastatin and niacin) sold by Merck, CADUET ™ (atorvastatin calcium and amlodipine besylate) sold by Pfizer and SIMCORMR (simvastatin and niacin) sold by Merck. These combination products with commercially available statins are sold as film-coated tablets.

The shape and size of the solid dosage form may vary according to the invention. The shape of the capsule may be, but is not limited to, round, oval, oblong or a non-standard shape. The solid dosage form is sized to be less than the total internal volume of the soft gelatin capsule.

The solid dosage form can be coated with one or more coatings, including but not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings, moisture protection coatings and combinations thereof. The one or more coatings on the solid dosage form are useful to provide a controlled release of an active ingredient in the solid dosage form, protect the solid dosage form from the interactions with the liquid filling phase, or supply one or more active ingredients. Preferably, the solid dosage form is film coated. The one or more coatings on the solid dosage form can be applied by any conventional coating technique recognized in the pharmaceutical industry, including, but not limited to, tray coating, fluid bed coating or spray coating. Optionally, the coated or uncoated solid dosage form can be wrapped in gelatin film according to conventional tablet wrapping techniques.

Typical immediate release coating films are hydro-alcoholic film coatings or cellulose film coatings systems as used in various oral solid dosage dosage forms. Typical coating systems may be aqueous, alcohol based or organic solvent or combinations containing hydroxypropyl methyl cellulose and derivatives, and polyvinyl alcohol and derivatives.

Typical protective coatings may include, but are not limited to, antioxidants, chelating agents, colors or dyes.

Typical delayed-release or enteric coatings of the solid dosage form may consist of, but are not limited to, one or more of the following recognized coating agents: copolymers of methyl acrylate-methacrylic acid, succinate of. cellulose acetate, hydroxy propyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, sodium alginate / alginic acid and stearic acid.

Sustained release tablets can be film coated, enteric coated or formulated with polymer matrix. Sustained-release film coatings can include, but are not limited to, a water-insoluble material such as wax or wax-like substance, fatty alcohols, shellac, zein, hydrogenated vegetable oils, water-insoluble celluloses, acrylic acid polymers and / or methacrylic, and any other slowly digestible or dispersible solids known in the art.

Moisture protection coatings provide moisture barriers for moisture sensitive or hygroscopic drugs. Such coatings can be applied to solid dosage forms to protect the solid dosage form from moisture resulting from, for example, the soft gelatin encapsulation process which uses water as a primary processing aid and plasticizer of the gelatin or Functional polymer capsule cover system. The present invention can incorporate the solid dosage form coated with a suitable coating, such as gelatin and other polymers to increase the barrier properties of the solid in the liquid phase. Examples of dosage forms that incorporate moisture protection coating include, but are not limited to, calcium atorvastatin.

The liquid-filling phase of the soft gelatin capsule is lipophilic and comprises one or more oils to carry the solid dosage form which are compatible with the soft gelatin shell and do not interfere with or degrade the solid dosage form. The lipophilic liquid filler phase may be a therapeutic oil, an oil form of an active ingredient, an active ingredient or a preparation of multiple active ingredients which may be solutions, suspensions, emulsions, micro-emulsions, self-emulsifying systems, and other liquids that will be known by those who are experts in the field of soft gelatin capsule formulation. Examples of useful oils include omega-3 fatty acids, vegetable oils, mineral oils, other food grade oils and other pharmaceutically acceptable oils. Vegetable oils may include, but are not limited to, castor bean oil, coconut oil, peanut oil, palm kernel oil, canola oil, avocado oil, donut boil oil, bran oil. rice, borage oil, sunflower oil, soybean oil, palm oil, corn oil, olive oil, pumpkin seed oil, grape seed oil, sesame oil, argan oil and safflower oil. The preferred oils are triglycerides of omega-3 fatty acid, fatty acid ester of omega-3, or an emulsified formulation of omega-3 fatty acids. Examples of omega-3 fatty acids include alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The omega-3 fatty acids can be a refined combination of EPA and DHA derived from natural sources such as fish or algae, or a purified form of EPA or DHA. The extender oils may include vegetable oils, mineral oils, other food grade oils and other pharmaceutically acceptable oils.

The fillers may also include excipients known in the soft gelatin encapsulation art, such as dispersants, surfactants, plasticizers, flavoring agents, opacifying agents, preservatives, brittleness inhibiting agents, dyes, dyes and pigments, and disintegrants.

The filling formulation can be prepared using established procedures employed for the manufacture of pharmaceutical solutions, suspensions and semi-solids, and recognized by those skilled in the field of soft gelatine formulation.

The liquid phase or coating may also contain one or more active ingredients. The solid dosage form may comprise a combination of a statin compound and another active pharmaceutical ingredient. The present invention contemplates the use of any of the active ingredients known in the art. It is well within the knowledge of a person skilled in the art to select a particular combination of active ingredients or medicaments. In some embodiments, the active ingredients may include, but are not limited to, the following: APIs, nutraceuticals, nutritional supplements, therapeutic substances and functional excipients.

APIs may include, but are not limited to, the following: analgesics, anti-inflammatory agents, anti-helmintics, anti-arrhythmic agents, anti-asthmatic agents, anti-bacterial agents, antiviral agents, anti-coagulants, anti-dementia, anti-inflammatory agents -depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, antimalarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, antiprotozoal agents, anti-drugs -pyretic antithyroid agents, antitussives, anxiolytics, sedatives, hypnotics, neuroleptics, neuroprotective agents, beta-blockers, cardiac inotropic agents, cell adhesion inhibitors, corticosteroids, modulators of cytokine receptor activity, diuretics, anti-Parkinson agents, agents gastrointestinal, H-histamine receptor antagonists, HMG-CoA reductase inhibitors, keratolytics, agents that re gulan lipids, muscle relaxants, nitrates and other anti-angina agents, non-steroidal anti-asthma agents, nutritional agents, opioid analgesics, sex hormones, stimulants and anti-erectile dysfunction agents.

Nutraceuticals may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutarates, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium dichroxide, glandular products, glucosamine HC1, glucosamine sulfate, hydroxyl methyl butyrate, immunoglobulin, lactic acid , L-Carnitine, liver products, malic acid, maltose-anhydrous, mannose (d-mannose), methyl sulfonyl methane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage , theobromine, vanadyl sulfate and yeast.

Nutritional supplements may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or a combination thereof.

Vitamins may include, but are not limited to, the following: ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3) ), orotic acid, para-aminobenzoic acid, pantothenatos, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamin (vitamin Bl), tocotrienols, vitamin A, vitamin D, Vitamin E, vitamin F, vitamin, vitamin oils and oil-soluble vitamins.

Herbal supplements may include, but are not limited to, the following: arnica, cranberry, cimicaria, cat's claw, chamomile, echinacea, ass herb oil, fenegreco, linseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, rod of St. Joseph, hawthorn, kava-kava, licorice, arzol, psyllium, rauowolfia, sena, soy, St. John's wort, palm heart, turmeric, valerian.

Minerals may include, but are not limited to, the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum , phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc and other minerals.

Preferred nutritional supplements include, but are not limited to, the following: B vitamins and vitamin B complex, beta-carotene, calcium, collagen, Co-Q-10, rapan, echinacea, flax seed oil, folic acid, garlic, ginger, glucosamine, chondroitin, green tea, iron, lecithin, lutein, lycopene, magnesium, melatonin, arzol, niacin, omega-3 o potassium, probiotics, hearts of palm, selenium, St. John's wort, tocopherols, valerian, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, zinc and combinations thereof. Preferred nutritional supplement combinations include: Co-Q-10 and Omega-3 o Echinacea, garlic and ginger; glucosamine and chondroitin; vitamin D and calcium; vitamin D, calcium and magnesium; vitamin D, calcium, magnesium and zinc; and vitamin E and other tocopherols.

The shape and size of the soft gelatin capsules may vary according to the invention. The shape of the capsule may be, but is not limited to, round, oval, oblong or a non-standard shape. The typical soft gelatin dosage form forms and sizes may be, but are not limited to, those, as shown in Table 1. The invention provides the ability to incorporate into the soft gelatin capsule a wide range of components of solid dosage (shape and shaping) to manufacture an infinite variety of shapes and sizes of soft gelatine capsules.

Table 1 - Forms and Sizes of Soft Gelatin Capsule Nominal The soft gelatin capsule shell can be formed of plasticized gelatin or other functional polymeric materials which are typically used for the encapsulation of liquids, fluids, pastes and other fillers.

The outer shell of the soft gelatin capsule can be coated with one or more coatings, including but not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings and combinations of the same. The one or more coatings of the outer shell of the soft gelatin capsule may be useful to provide a controlled release of the soft gelatin capsule, protect the soft gelatin shell from degradation, or provide one or more active ingredients that may be the same or different from those in the liquid phase and the solid dosage form. Alternatively, additives such as pectin or synthetic polymers can be incorporated into the soft gelatin capsule shell to slow dissolution upon ingestion. Such coatings or additives to the cover phase of soft gelatin are well described in the literature and known to those skilled in the art. The outer shell of one or more coatings of the soft gelatin capsule can be applied by any conventional technique, including, but not limited to, tray coating, fluid bed coating or spray coating.

The soft gelatin capsules of the present invention can be prepared according to the following methods. An apparatus as described in Canadian Patent Application No. 2,706,272 can be used to manufacture the soft gelatin capsule of the present invention.

One embodiment of the present invention can be prepared by providing a preformed film-coated tablet comprising a statin compound or statin compound in combination with at least one active ingredient. Then a first cover part of the soft gelatin capsule is provided. The tablet coated with preformed film is introduced into the first cover part of the soft gelatin capsule. A second cover part of the soft gelatin capsule is provided. The first and second cover portions of the soft gelatin capsule move together at one end to form a cavity. At least one liquid phase is introduced into the cavity. Then the first and second cover portions of the soft gelatin capsule are sealed to form the soft gelatin capsule of the present invention.

Individual or multiple liquid phases can be introduced into the capsule by means of a single, double or multiple wedge design that facilitates the filling of the capsule in situ of multiple phases.

The liquid filling phase may include different liquid phases that are placed side-by-side in the soft gelatin capsule. Each layer phase can incorporate an active ingredient or multiple active ingredients.

Figure 1 illustrates soft gelatin capsules 140 of the present invention containing a solid round tablet 130. A solid round tablet preformed for comparison is also shown.

Soft gelatin capsules containing solid and liquid phases according to the invention provide a number of significant benefits for the administration of active ingredients.

The multi-phase soft gelatin dosage form of the present invention can be used to deliver two or more active ingredients that would otherwise interact with each other. One or more active ingredients are dissolved in the liquid filling phase and the other active ingredient (s) in the solid dosage form.

Another use of the present invention is to provide effective control of the release of single or multiple APIs introduced into the solid dosage form and the liquid phase. The liquid phase provides the immediate release capacity of the API in the liquid phase by virtue of a solution, pre-dispersed formulation or self-emulsifier. The solid phase can be coated to provide the delayed release of API in the solid phase.

When two or more capsules and / or tablets are prescribed, their combination in a dosage form provides benefits to the patient and advantages of convenience and cost administration.

The present invention can be useful as a polypill. A polypill is a medication that contains a combination of active ingredients, which reduces the number of tablets or capsules that need to be taken. Combined medications in the form of a polypill are useful for the treatment of cardiovascular disease and diabetes.

The present invention can reduce problems, such as the time and cost, associated with the combination, of two or more APIs in a dosage form. New combinations in a dosage form require the development of new formulations and require pharmaceutical and clinical studies to demonstrate safety, efficacy and potency. The present invention provides the ability to incorporate more than one API into a unit dosage form using established API 'forms or APIs that may be in the liquid or solid phase. The present invention allows the retention of the tablet, tablet or capsule form established from an API. This provides the ability to retain the pharmaceutical characteristics of the solid dosage form in combination with a liquid or fluid phase. Key features include: physical and chemical stability, release profile of tablet or tablet API, bioavailability and clinical performance. The retention of established clinical performance by incorporating the original solid may obviate the need to conduct extensive phase III clinical trials that would otherwise be required with a new formulation.

By combining a number of established, off-patent or generic medications, the present invention can be useful for treating cardiovascular conditions and provides the low-cost treatment prospectus.

The present invention may be useful for the combined administration of unit doses of HMG-CoA inhibitors (statins) and omega-3 fatty acids. Statins may be in the form of tablets or capsules containing the HMG-CoA inhibitors, a single ingredient, or statins in combination with other active ingredients.

The present invention may allow the use of a smaller dosage form than those commercially sold. Encapsulation of a solid dosage form in a soft gelatin capsule provides protection against dissolution of the solid dosage form before reaching the proposed target site. Thus, an encapsulated solid dosage form may not need to be as durable as it is compared to commercially available solid dosage forms. The present invention can reduce the need for excipients that function to prevent early dissolution of the solid dosage form when ingested, allowing the use of a smaller and more economical solid dosage form.

The following are examples of the benefits of the present invention for the administration of drug combinations which may be in the form of a solid dosage form and liquid filling phase in a soft gelatin capsule.

EXAMPLES EXAMPLE 1: Preparation of Calcium Atorvastatin (Dosage Form Solid) and Ornega 3 Oil (Liquid Phase) A tablet coated with preformed calcium atorvastatin film (commercially sold as LIPITOR® by Pfizer) is provided. Then a first cover part of the soft gelatin capsule is provided. The tablet coated with preformed film is introduced into the first cover part of the soft gelatin capsule.

A second cover part of the soft gelatin capsule is provided. The first and second cover part of the soft gelatin capsule move together at one end to form a cavity. At least one liquid phase is introduced into the cavity. Then the first and second cover portions of the soft gelatin capsule are sealed to form the soft gelatin capsule of the present invention.

EXAMPLE 2: Calcium Atorvastatin (Solid Dosage Form) and Oil Omega 3 (Liquid Phase) A soft gelatin dosage form of the present invention may include the following composition: Ingredient mg / soft gel A. Solid Phase Atorvastatin Tablet 152.8 Calcium Lipitor® coated with film (10 mg of atorvastatin) B. Liquid Phase Oil Omega-3 Alta 1000.00 Power (37% DHA, 46% EPA) Total Fill Weight 1091.30 EXAMPLE 3: Calcium Aatorvastatin (Solid Dosage Form) and Omega 3 Oil (Liquid Phase) A soft gelatin dosage form of the present invention may include the following composition: Ingredient mg / soft gel A. Solid Phase Atorvastatin Tablet 152.8 Calcium Lipitor® Coated with film (10 mg of atorvastatin) B. Liquid Phase Oil Omega-3 Alta 1000.00 Power (EPA (70% esters ethyl)) Total Fill Weight 1091.31 EXAMPLE 4: Calcium Rosuvastatin (Solid Dosage Form) and Oil Omega 3 (Liquid Phase) A soft gelatin dosage form of the present invention may include the following composition: Ingredient mg / soft gel A. Solid Phase Rosuvastatin tablet 155.30 Calcium Crestor® coated with film (5 mg of resuvastatin) B. Liquid phase Oil Omega-3 Alta 1000.00 Power (37% DHA, 46% EPA) Total Fill Weight 155.30 EXAMPLE 5: Comparative Stability Data To illustrate how the soft gelatin dosage form of the present invention provides improved stability, the potency of atorvastatin in the soft gelatin dosage forms of the present invention as described in Examples 2 and 3 above, was compared to to a commercial tablet of calcium atorvastatin (Lipitor®). In Example 2, a tablet of Lipitor® calcium atorvastatin calcium and high potency omega-3 oil (37% DHA and 46% EPA) are incorporated into a soft gelatin capsule. In Example 3, a Lipitor® calcium atorvastatin tablet and high potency omega-3 oil (EPA (70% ethyl esters)) are incorporated into a soft gelatin capsule.

The stability of the soft gelatin capsules was determined using a gradient UPLC analysis with a standard reference of Lipitor® Caloric Atorvastatin Tablet. Samples of the soft gelatine dosage forms, in Examples 2 and 3 above were tested under accelerated conditions for the intervals as described in the following table. The examples below demonstrate that the potency of Lipitor® calcium atorvastatin tablets incorporated in the dosage form of the present invention is stable for 6 months relative to a Lipitor® atorvastatin calcium tablet.

EXAMPLE 6: Dissolution data The dissolution profile of five soft gelatin capsules of the filling composition described in Example 2 was determined using the dissolution apparatus of USP # 2, 0.05M phosphate buffer, 6.8, pH 6.8, at 37 ° C as a medium of dissolution with a blade speed of 75 rpm.

Drug release was determined by UPLC using a UV detector at 245 nm.

The dissolution results are presented in the table below.

In view of the teachings presented herein, other modifications and variations of the present inventions will be readily apparent to those skilled in the art. The above discussion and description are illustrative of some embodiments of the present invention, but are not intended to be limitations on the practice thereof.

Any of the patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. These patents and publications are hereby incorporated by reference to the same extent as if each individual publication was specified and individually indicated that is incorporated by reference.

Claims

1. A multi-phase soft gelatin capsule for oral administration, the soft gelatin capsule characterized in that it comprises: at least one preformed solid dosage form comprising a statin compound; Y at least one liquid filling phase comprising omega-3 fatty acids; wherein the at least one solid dosage form and the at least one liquid filling phase are independently introduced into the soft gelatin capsule.

2. The soft gelatin capsule according to claim 1, characterized in that the at least one preformed solid dosage form is a finished dosage form of pharmaceutical grade.

3. The soft gelatin capsule according to any of claims 1 to 2, characterized in that the at least one preformed solid dosage form is selected from the group consisting of a tablet, a tablet, a capsule, a portion of solid material and a granule

4. The soft gelatin capsule according to any of claims 1 to 3, characterized in that the at least one liquid filling phase further comprises at least one additional active ingredient.

5. The soft gelatin capsule according to claim 4, characterized in that the at least one additional active ingredient is selected from the group consisting of: an active pharmaceutical ingredient, nutraceutical, nutritional supplement, therapeutic substance, functional excipients and combinations thereof .

6. The soft gelatin capsule according to any of claims 1 to 5, characterized in that the at least one liquid filling phase further comprises extender oils.

7. The soft gelatin capsule according to claim 6, characterized in that the extender oils comprise vegetable oils, mineral oils, food grade oils, pharmaceutically acceptable oils or mixtures thereof.

8. The soft gelatin capsule according to any of claims 1 to 7, characterized in that the statin compound is selected from the group consisting of: atorvastatin, fluvastatin, lovastatin, pitavastatin, provastatin, rosuvastatin, simvastatin and pharmaceutically acceptable salts thereof .

9. The soft gelatin capsule according to claim 8, characterized in that the statin compound is atorvastatin calcium.

10. The soft gelatin capsule according to claim 8, characterized in that the statin compound is fluvastatin sodium.

11. The soft gelatin capsule according to claim 8, characterized in that the statin compound is pravastatin sodium.

12. The soft gelatin capsule according to claim 8, characterized in that the statin compound is rosuvastatin calcium.

13. The soft gelatin capsule according to any of claims 1 to 7, characterized in that the statin compound further comprises at least one additional active ingredient.

14. The soft gelatin capsule according to claim 13, characterized in that the at least one additional active ingredient is an active pharmaceutical ingredient.

15. The soft gelatin capsule according to claim 13, characterized in that the statin compound is simvastatin and the at least one additional active ingredient is exoimimibe.

16. The soft gelatin capsule according to claim 13, characterized in that the statin compound is lovastatin and the at least one additional active ingredient is niacin.

17. The soft gelatin capsule according to claim 13, characterized in that the statin compound is atorvastatin calcium and the at least one additional active ingredient is amlodipine besylate.

18. The soft gelatin capsule according to claim 13, characterized in that the statin compound is simvastatin and the at least one additional active ingredient is niacin.

19. The soft gelatin capsule according to any of claims 1 to 18, characterized in that the at least one preformed solid dosage form has at least one coating.

20. The soft gelatin capsule according to claim 19, characterized in that the at least one coating on the at least one preformed solid dosage form is selected from the group consisting of: immediate release coatings, protective coatings, enteric coatings or of delayed release, sustained release coatings, barrier coatings, moisture protection coatings, and combinations thereof.

21. The soft gelatin capsule according to any of claims 19 to 20, characterized in that the at least one coating on the at least one preformed solid dosage form is selected from the group consisting of: film coatings, gelatin coatings and combinations thereof.

22. The soft gelatin capsule according to any of claims 19 to 21, characterized in that the at least one coating on the at least one preformed solid dosage form further comprises at least one active ingredient.

23. The soft gelatin capsule according to claim 22, characterized in that the active ingredient is selected from the group consisting of: an active pharmaceutical ingredient, neutraceutical, nutritional supplement, therapeutic substance, functional excipients and combinations thereof.

24. The soft gelatin capsule according to any of claims 1 to 23, characterized in that the omega-3 fatty acids comprise triglycerides, ethyl esters or an emulsified formulation of the omega-3 fatty acids.

25. The soft gelatin capsule according to claim 24, characterized in that the omega-3 fatty acids comprise eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or a mixture thereof.

26. the soft gelatin capsule according to any of claims 1 to 25, characterized in that the soft gelatin capsule has at least one coating.

27. The soft gelatin capsule according to claim 26, characterized in that the at least one coating on the soft gelatin capsule is selected from the group consisting of: immediate release coatings, protective coatings, enteric or delayed release coatings, coatings of sustained release, barrier coatings, and combinations thereof.

28. The soft gelatin capsule according to any of claims 26 to 27, characterized in that the at least one coating on the soft gelatin capsule further comprises at least one active ingredient.

29. The soft gelatin capsule according to claim 28, characterized in that the active ingredient is selected from the group consisting of: an active pharmaceutical ingredient, nutraceutical, nutritional supplement, therapeutic substance, functional excipients and combinations thereof.